ROLE OF CHEMOTHERAPYINIMPROVING DYSPHAGIA FREE SURVIVALIN PATIENTS WITH ADVANCED ESOPHAGEAL CANCERTREATED WITH HIGH DOSE RATE BRACHYTHERAPY
ROLE OF CHEMOTHERAPY
IN
IMPROVING DYSPHAGIA FREE SURVIVAL
IN PATIENTS WITH ADVANCED ESOPHAGEAL CANCER
TREATED WITH HIGH DOSE RATE BRACHYTHERAPY
By
EMILIA OLIMPIA TIMOTIN, BSc
A Thesis
Submitted to the School of Graduate Studies
in Partial Fulfillment of the Requirements for the Degree of
Master of Science
McMaster University
Master of Science McMaster University
(Medical Physics and Hamilton, Ontario
Applied Biology)
TitleRole of Chemotherapy in Improving Dysphagia Free Survival in Patients with Advanced Esophageal Cancer Treated with High Dose Rate Brachytherapy
Author Emilia Olimpia Timotin
Supervisor Dr. Ranjan K Sur
Dr. Thomas Farrell
Number of Pages104
ABSTRACT
BACKGROUND
High dose rate Intraluminal Brachytherapy (HDRILBT) is one of the most used palliative treatment options for advanced esophageal cancer. The present study evaluates the role of additional chemotherapy in improving dysphagia free survival (DFS) and overall survival (OS) in patients with inoperable advanced esophageal cancer treated with brachytherapy.
MATERIAL and METHODS
132 patients with advanced metastatic esophageal cancer with total or near total dysphagia were given HDRILBT to a dose of 18 Gray (Gy) in 3 fractions on alternate days. Intraluminal brachytherapy alone was performed on 98 patients. 34 patients received Epirubicin, 5-Fluorouracil, and Cisplatin (ECF) chemotherapy regimen after HDRILBT. The mean age of the whole group was 65 years (HDRILBT-71.41, HDRILBT+ECF-59.98; p<0.0001). Male: Female was 101:31 (HDRILBT 72:26; HDRILBT +ECF 29:5; p>0.05). The location incidence was GEJ: Lower Esophagus: Mid Esophagus: Cervical Esophagus 24:81:17:5 respectively; for the whole group HDRILBT- 17:57:16:4; HDRILBT+ECF-7:24:1:1; p>0.05. 78 patients presented with co-morbidities (cardiac) (HDRILBT- 59; HDRILBT+ECF- 19; p>0.05). 74 patients presented with distant metastasis (54 with HDRILBT and 20 with HDRILBT+ECF; p>0.05). The ECOG scores were as follows 0:1:2:3:4 15:52:51:12:2 (HDRILBT- 10:35:41:10:2; HDRILBT+ECF- 5:17:10:2:0; p=0.0014). All patients completed 3 fractions of HDRILBT. 34 patients received additional chemotherapy with ECF regimen. Selection of patients was done by the medical oncologist. Statistical analysis of data was done using the SAS statistical analysis software system. Univariate and multivariate analysis was done using the log rang test.
RESULTS
Patients who received additional ECF were younger (p< 0.001) and with a better performance status than those who received HDRILBT alone (p=0.0014). Mean DFS was higher for patients who had further chemotherapy treatment (232 days) vs. patients who had HDRILBT only (155 days) (p>0.05). The mean OS for HDRILBT + ECF was 266 days (p = 0.0010) compare with HDRILBT alone which was 155 days, when the effect of 10 prognostic factors was analyzed for DFS and OS. Only additional ECF after brachytherapy impacted on DFS while age (p<0.001) and performance status (p=0.0014) impacted on overall survival on univariate analysis. On multivariate analysis tumor length and nodal presentation (p<0.000) impacted on OS. The incidence of stricture and fistulae were similar. Chemotherapy related side effects: gastrointestinal tract (25 patients), neurotoxicities (2) and nephrotoxicities (2) were seen as a result of 5-FU and Cisplatin respectively. 18 patients completed at least 3 cycles of ECF.
CONCLUSION
Additional chemotherapy with ECF after HDRILBT improves the DFS and OS in selected patients with advanced esophageal cancer. These patients tend to be younger with better performance status, small tumor length and nodal metastasis. The incidence of complications is similar with more than 50% patients completing at least 3 cycles of chemotherapy.
ACKNOWLEDGEMENTS
I would never have been able to finish my thesis without the guidance ofmy committee members, help from friends, and support from my family.
First and foremost I would like to express my deepest gratitude to my advisor, Dr. Ranjan K. Sur. Without his vision and initiative, this research would have not been done. I am thankful for his aspiring guidance, invaluably constructive criticism and friendly advice during the project work. Many thanks for offering me the opportunity to conduct this study, for his excellent guidance, for mentoring me throughout this endeavor, for his enthusiasm.
Nonetheless my gratitude goes to my supervisor Dr. Thomas Farrell for sharing his truthful and illuminating views on a number of issues related to the project. I am grateful that he provided the necessary support for me to gain confidence in myself. I am sincerely grateful to him for patiently corrected my writing, for his motivation, insightful comments, support and immense knowledge.
As always, for believing in me and for her support, my sincere appreciation goes to my manager Marcia Smoke.
I would also like to thank Bernard Donde for his help and guidance in data analysis.
Special thanks go to Dr. Colin Seymour who was willing to participate in my final defense committee at the last moment.
I would like to thank Christine Pinho, who as a good friend was always willing to help and give her best suggestions. It would have been a lonely work without her.
Many thanks to my colleagues and friends at work especially Michele Cardoso and Lilian Doerwald-Munoz who contributed with encouraging words and comforting words and kept me going. My research would not have been possible without their help.
Last but not least, I would like to offer my deeply thanks to my husband and two children Antonia and Titus for their patience and tremendous help during this time. They were always supporting me and encouraging me with their best wishes. Thank you for being there for me throughout my life and supporting my every decision.
TABLE OF CONTENTS
Abstract iv
Acknowledgments vi
Table of Contents vii
List of Illustrations, Chart, and Diagrams ix
List of Abbreviations, and Symbols xii
1.0 Introduction
1.1 Esophageal cancer 1
1.1.1 Incidence and Mortality in North America and Worldwide 3
1.1.2 Risk Factors 6
1.1.3 Pathology 10
1.1.4 Presentation 11
1.1.5 Factors Affecting Prognosis 12
1.1.6 Diagnostic Work-up 13
1.1.7 Assessment and Staging 15
1.2 Treatment Options 19
1.3 Objectives and Aims 22
1.4 Hypotheses of the Study 23
1.5 Review of Literature 24
1.5.1 The role of brachytherapy in palliation of dysphagia 25
1.5.2 The role of chemotherapy in metastatic esophageal cancer 33
2.0 Patients and Methods 52
3.0 Results 62
4.0 Discussion 77
5.0 Conclusion 81
6.0 Reference List 82
LIST OF FIGURES AND TABLES
Figure 1.1 Anatomy of the esophagus 1
Figure 1.1.6.1 Advanced esophageal cancer: A, Near total obstruction;
B, Barium swallow x-ray 14
Figure 1.1.7.1Esophageal Cancer Staging 15
Figure 2.8Remote AfterloaderBrachytherapy Unit 55
Figure 2.9Barium swallow examination of an complete tumor 55
obstracted esophagus
Figure 2.10 Localization of Intra-oral tube/Catheter in situ 56
Figure 2.11 Marker wire used to measure the tumor length. 57
Figure 2.12 Diagram showing definition of the target volume 57
Figure 2.13Treatment Plan Distributions 58
Figure 3.1Pie graph showing age distribution of patients 65
Figure 3.2Pie graph showing gender distribution of patients 66
Figure 3.3Pie graphs showing male and female distribution of 66
patients studied for each treatment strategy
Figure 3.4Pie graph showing tumor location 67
Figure 3.6Pie graph showing tumor pathology 68
Figure 3.7Distribution of Nodal Metastasis for patient receiving 69
HDRILBT only
Figure 3.8 Distribution of Nodal Metastasis for patient receiving 69
HDRILBT plus Chemotherapy
Figure 3.9Distant Metastases 70
Figure 3.10Distribution of treatment given and number of patients 71
Figure 3.12Dysphagia Free Survival DFS 72
Figure 3.13Overall Survival OS 74
Table 1.1.2.1Esophageal cancer risk factors 6
Table 1.1.4.1Dysphagia Grading 11
Table 1.1.7.2TNM 7th Edition of the AJCC Cancer Staging Manual: 17
Esophagus and Esophagogastric Junction
Table 1.1.7.3A7th Edition of the AJCC Cancer Staging Manual; 18
Adenocarcinoma stage grouping
Table 1.1.7.3B7th Edition of the AJCC Cancer Staging Manual; 18
Squamous-cell carcinoma stage groupings
Table 1.2.1Palliative Treatment Methods for Advanced Esophageal 19
Cancer
Table 1.2.2Methods of Palliation and Median Survival 21
Table 1.2.3Comparison between treatment modalities for dysphagia 21
relief
Table 1.5.1.1High Dose Rate Brachytherapy – Palliative Results 26
Table 1.5.2.1Old single chemotherapy agents 34
Table 1.5.2.2New single chemotherapy agents 37
Table 1.5.2.3Combination of two chemotherapy agents 45
Table 2.1EORTC-QLQ 53
Table 2.2Dysphagia algorithm 54
Table 2.3Clinical Patient Characteristics 62
Table 2.4Tumor Characteristics and Treatment Features 63
Table 2.6WHO/ECOG 64
Table 2.7Study Patients’ Performance Status 64
Table 3.5Tumor Pathology 68
Table 3.11Dysphagia free survival for both treatment modalities 72
Table 3.14Overall survival for both treatment modalities 74
Table 3.15Complications for both treatment modalities 76
Table 3.16Total numbers of toxicities for both treatment modalities
together 76
Table 4.1Review HDRILBT with literature 77
LIST OF ABREVIATIONS
HDRILBTHigh Dose Rate Intraluminal Brachytherapy
ECFEpirubicin, Cisplatin, 5- Fluorouracil
EORTC-QLQEuropean Organization for Research and Treatment of Cancer Quality of Life Questionnaire
WHOWorld Health Organization
ECOG Eastern Cooperative Oncology Group
DFSDysphagia Free Survival
OSOverall Survival
SCC Squamous Cell Carcinoma
AC Adenocarcinoma
CT Computed Tomography
PET Positron Emission Tomography
EUS Endoscopic Ultrasound
HRQoL Health Related Quality of Life
GEJGastro-esophageal Junction
1
1.0 INTRODUCTION
1.1ESOPHAGEAL CANCER
The esophagus is a long hollow tubed organ that is lined with stratified squamous epithelium and has the main function of passing food from the mouth to the stomach. Several layers of tissue make up the wall: the mucosal layer, submucosal layer, muscular layer and the adventitia layer (Figure 1.1).
The uncontrolled division of abnormal cells leads to cancer. This cell growth and development remains unregulated and will develop into a tumor. The cells can enter the blood stream or lymphatic system and as a result can spread to other organs. This process is known as metastasis.
Figure 1.1 - Anatomy of the esophagus [3]
Esophageal cancer is a gastrointestinal malignant tumor that forms in esophagus tissue. It has an insidious onset and a poor prognosis. On average, for tumors under 5cm long, 30% are localized, 40% are locally advanced and 30% have undergone metastasis [19]. For tumors longer than 5cm, 10% remain localized, 25% become locally advanced and 70% undergone distant metastasis [19]. The spread occurs from the inside of the esophagus, outwards through several layers of tissue. Among many presenting symptoms experienced by patients, dysphagia is the most predominant. Dysphagia is defined as difficulty in swallowing caused by a lesion or a stricture, leading to an obstruction of the esophagus by a tumor. When dysphagia to solid food occurs, the esophagus is almost completely obstructed with 90% of the lumen compromised and the muscularis mucosa has been penetrated by the tumor into the adventitia.
One of the major concerns with esophageal cancer is the poor prognosis in the majority of cases. Almost all patients have advanced disease at the time of initial consultation [19].
1.1.1 INCIDENCE AND MORTALITY IN ESOPHAGEAL CANCER IN NORTH AMERICA AND WORLDWIDE
INCIDENCE AND MORTALITY IN NORTH AMERICA
The incidence of esophageal cancer has been steadily increasing over the past decades worldwide [19]. In North America in 2013 the incidence of new cases of esophageal cancer was estimated to be around 2000 from all Canadians [22]. The number of Canadians with esophageal cancer who will die from the disease has been approximated to be around 1900 [22]. Annually this number has been increasing at a steady rate with a change in histologic type of esophageal cancer and the location of the primary tumor [19].
Esophageal cancer is amongst the 10 most common causes of cancer death in men with an estimated percentage of 5-7%. A five-year relative survival rate is approximately 38% when the disease is localized, 20% for regional and 3% for metastasis. These survival rates for esophageal cancer pertain to squamous cell carcinomas and adenocarcinomas together [142].
Esophageal cancer can be either squamous cell carcinoma or adenocarcinoma. The most common histological form of cancer in the esophagus has long been the squamous cell carcinoma type. For the last ten years, reports have shown a rising incidence of esophageal adenocarcinoma in most of the western world, and an unchanged percentage in Asia and South America [122]. It had been largely thought that esophageal adenocarcinoma, for the most part, did not exist until the 1950's. Lately it has been one of the fastest growing cancers in America [116, 97, 2]. For different types of esophageal cancer,squamous cell carcinoma has been seen commonly in blacks and white women while adenocarcinoma among white men.
The primary tumor location was more frequently in the distal esophagus. Squamous cell carcinoma occurred mostly in the upper third or middle of the esophagus. Adenocarcinomas were predominant in lower third of the esophagus and gastro-esophageal junction [24, 50].
The incidence rates have increased from 1996 to 2009 by 0.5% in all races. This has happened because of an increased incidence in men. In woman, the incidence actually had dropped by 0.4% [99]. The incidence of blacks have been shown to be twice that of whites (8.63/100000 vs. 4.39/100000, p<0.05) [35].
Esophageal cancer has occurred 3-4 times more often in males than females [24, 50]. Keighley study showed the same result with male to female ratio of 3 to 1 [74].
In Asia men and women ratio had been almost equal [75].
As per Canadian Cancer Society statistics, in Canada it was estimated that 1,550 men and 460 women were diagnosed with esophageal cancer in 2013 [22].
The risk of esophageal carcinoma, for both squamous cell carcinomas and adenocarcinomas, has increased with age. The mean age at diagnostic was seen to be 67 years [35].
Esophageal cancer is seen all around the world. The geographic difference in cancer of the esophagus suggests that the environmental exposure plays an important role.
Blot et al showed that squamous cell carcinoma is the most frequent histological type of esophageal cancer. Additionally, they concluded that the incidence of adenocarcinoma of the esophagus and esophagogastric junction has been rising especially in US and Europe among white men [12].
The same conclusion was confirmed by studies of Pera et al. They reported a shift in the histology of esophageal cancer in the western countries and the location of the tumor being more frequent in the distal esophagus [105]. In contrary, it was seen an unchanged incidence in this matter in Asia [47] and South America [44]. In 90% of cases of esophageal cancer in central Asia to North - Central China, squamous cell carcinomas had been predominant [54, 134]. Furthermore, it was observed an incidence pattern change because of immigrants that are adjusting correspondingly to where they live [135].
INCIDENCE AND MORTALITY WORLDWIDE
The top five cancers that kill are lung, colon, breast, prostate and pancreas. Cancer related deaths are liver cancer at 3%, ovarian cancer with 2.7%, esophageal cancer having 2.4%, bladder cancer 2.4% and brain cancer with 2.3% incidence rates. In combination, these account for 69.1% of all deaths related to cancer [122].
Esophageal cancer is detected in approximately half a million people every year worldwide and the incidence is increasing unfortunately very fast [103]. It is the eighth most common cancer and the sixth most common cause of cancer death [101]. Surgical removal is no longer a viable treatment strategy for more than half of patients diagnosed with an advanced stage of esophageal cancer [116].
It also has been reported that the majority of esophageal cancer cases (80-85%) are diagnosed in developing countries; the predominant type is squamous cell carcinoma and it is the fourth most common cancer in men [18].
Incidence rates vary worldwide by about 16-fold where South and East Africa and East Asia are at the highest and Western and Middle Africa and Central America is the lowest [24, 50].
Worldwide, the survival rate of the esophageal cancer patient is poor because of advanced or inoperable disease at presentation. The disease has very aggressive nature and less than 15% of patients survive 5 years after initial diagnosis [74].
1.1.2 RISK FACTORS
The recognized main risk factors for esophageal cancer in general are smoking, excessive alcohol consumption, dietary factors mostly red meat consumption, gastro-esophageal reflux disease (GERD) and Barett’s esophagus [136] (Table 1.1.2.1). Lifestyle factors are associated with a risk of mucosal irritation and could promote tumor formation [34].
Table 1.1.2.1 - Esophageal cancer risk factors [42]
RISK FACTOR / SQUAMOUS CELL CARCINOMA / ADENOCARCINOMASmoking / +++ / ++
Alcohol consumption / +++ / -
Red meat consumption / + / +
Barnett’s esophagus / - / ++++
Reflux symptoms / - / +++
Being overweight / - / ++
Poverty / ++ / -
Caustic injury to the esophagus / ++++ / -
History of head and neck cancer / ++++ / -
History of radiotherapy / +++ / +++
Hot drinks consumption / + / -
-: No effect; +: Suspicious effect; ++: Positive effect; +++, ++++: Strong positive effect.
SMOKING AND ALCOHOL
Cigarette smoking had been long correlated with squamous cell carcinoma of the esophagus. A study reported that smoking and alcohol if consumed alone, it accounted for 87% of squamous cancers but if they were mixed they accounted for 50% of adenocarcinomas [138]. Lately, there were studies that correlated smoking with gastro-esophageal adenocarcinomas [125]. Sung et al. reported that the combination of cigarette and alcohol was associated with both squamous cell carcinoma and adenocarcinoma of esophagus, cardia, and proximal and distal gastric cancers. Engel and co-workers stated that low risk areas like U.S.A and other western countries had alcohol and smoking contributing to 90% of the cases [41].
Another risk factor noted, was chewing betel nut and betel leaf. It had been very common in India. Nayar et al., conducted a study and noticed that this tradition would increase the chance of getting esophageal cancer by 3.16 times [100].
INFECTIOUS FACTORS
Viral Agents:
The risk of Human Papilloma Virus (HPV) infection was not clear, but it was believed that it was linked with the development of squamous cell carcinoma [39, 73].
Fungal Agents:
There had been studies, which showed a potential association between fungi, most common candidaalbicans and esophageal cancer incidence [11].
Another factor taken in consideration by many studies was Helicobacter pylori [25, 148]. It has been noted that H. Pylori has actually a protective effect to adenocarcinoma but plays an opposite role, as a risk factor for squamous cell carcinoma.
GENETIC FACTORS
The researchers were questioning if genetic factors were linked with the development of esophageal cancer. There were not too many studies to prove the link. Akbari and his colleagues showed that familial and genetic factors play an important role as a risk factor for first-degree relatives of patients with esophageal cancer [5]. No particular genetic factors were recognized.
DIETARY FACTORS/ LOW SOCIO-ECONOMIC STATUS